title: Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3.
abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade < 8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.
authors.affiliation: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sara
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authors.lastname: Lindstrom
authors.forename: Fredrick
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authors.lastname: Schumacher
authors.forename: Afshan
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authors.lastname: Siddiq
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authors.initials: RC
authors.lastname: Travis
authors.forename: Daniele
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authors.lastname: Campa
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authors.lastname: Giovannucci
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authors.initials: CA
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authors.forename: Jytte
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authors.lastname: Halkjaer
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authors.forename: Mattias
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authors.lastname: Johansson
authors.forename: Rudolf
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authors.lastname: Kaaks
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Carmen
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authors.lastname: Navarro
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: Meir
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authors.lastname: Stampfer
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
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authors.forename: Dimitrios
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authors.lastname: Trichopoulos
authors.forename: Jarmo
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authors.lastname: Virtamo
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.forename: Meredith
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authors.lastname: Yeager
authors.forename: Brian
authors.initials: B
authors.lastname: Henderson
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Peter
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mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D004777:Environment; D004843:Epistasis, Genetic / Q000502:physiology; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor